PROJECT SUMMARY In 2014, UNAIDS introduced the ?90-90-90? targets for HIV control, including that 90% of those on ART are virologically suppressed. In order to reach these treatment goals, additional progress will need to be made in sub-Saharan Africa, where rates of 1st-line antiretroviral treatment (ART) failure are reportedly as high as 1 in 3 individuals and increasing rates of drug resistance are complicating efforts to effectively treat these patients. For patients experiencing virologic failure (VF) on 1st-line ART, there is currently uncertainty over which individuals should be maintained on their 1st-line ART regimen and who should be switched to a 2nd-line regimen. Multiple studies have indicated that traditional Sanger-based genotypic testing might not accurately predict clinical outcomes in these situations. VF commonly occurs in those taking regimens with a high genotypic susceptibility scores (GSS) as determined by standard Sanger sequencing techniques, and conversely, virologic suppression often occurs in patients on regimens with a low GSS. This study brings together an experienced team of clinical researchers, virologists, pharmacologists, and biostatisticians from the United States and Africa to determine the predictors of VF either with maintenance of 1st-line ART or after switch to 2nd-line ART. This study will leverage stored samples from existing clinical trials combined with innovative viral sequencing and pharmacologic technologies to assess the risk of VF with either approach. The proposed studies will directly address key knowledge gaps related to drug resistance and medication adherence, and are ultimately intended to improve the clinical management of patients with 1st-line ART failure in sub-Saharan Africa. Optimizing treatment strategies in this population is critical for preventing drug resistance, controlling the epidemic, and ensuring the long-term sustainability of HIV programs.